US 20180371542A1 (19 ) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018 /0371542 A1 Anton (43 ) Pub . Date : Dec . 27 , 2018 ( 54 ) OPIOID RECEPTOR BLOCKADE IN ( 52 ) U . S . CI. TREATING ALCOHOL USE DISORDERS CPC .. .. C12Q 1/ 6876 ( 2013. 01 ) ; A61K 31/ 485 ( 71) Applicant: MUSC Foundation for Research ( 2013 .01 ) ; C12Q 2600 / 106 ( 2013 .01 ) ; C12Q Development, Charleston , SC ( US ) 2600 / 156 ( 2013 .01 ) ; A61P 25 / 32 (2018 .01 ) ( 72 ) Inventor: Raymond F . Anton , Charleston (US ) (57 ) ABSTRACT ( 73 ) Assignee : MUSC Foundation for Research Development, Charleston , SC (US ) Provided are methods for treating alcohol use disorders using opioid receptor antagonists . In some embodiments , the (21 ) Appl. No. : 16 / 019 ,091 presently disclosed methods include assaying nucleic acid from a subject regarding the subject' s genotype with respect ( 22 ) Filed : Jun . 26 , 2018 to the COMT and OPRM1 genes and administering or not Related U . S . Application Data administering an opioid receptor antagonist to the subject on (60 ) Provisional application No . 62 /525 , 123 , filed on Jun . the basis therefore . Also provided are methods for detecting 26 , 2017 . susceptibility to an opioid receptor antagonist therapy for disorders associated with opioid receptor activity and meth Publication Classification ods for identifying and treating human subjects having (51 ) Int. Ci. susceptibility to opioid receptor antagonist therapies for C12Q 1 /6876 ( 2006 .01 ) A61K 31/ 485 (2006 . 01) disorders associated with opioid receptor activity . A61P 25 / 32 ( 2006 . 01 ) Specification includes a Sequence Listing . Patent Application Publication Dec. 27 , 2018 Sheet 1 of 7 US 2018 / 0371542 A1 . * * * . www . PPC * obiek SKS wwwwwwwwwwwwwwwwwww 0233 $ 100 W 3 8 : 353 & ss wwwhiteteretetettstetten : : : : : : : : : : : FIG . 1 Patent Application Publication Dec. 27 , 2018 Sheet 2 of 7 US 2018 / 0371542 A1 OPRM1.- . asn40 COMT158. Met Carrier Placebo n = 25 ** ** . ' ' . • Treatment.', Week 12 16 COMT158 Val /Val Valtrexone 3 = 12 FIG . 2A Patent Application Publication Dec. 27 , 2018 Sheet 3 of 7 US 2018 / 0371542 A1 OPRM1- asp40 ** * COMT158 Met Carrier . Paltrexone m = 27 2 .. : THE . .' : . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' ' : ' : : ' : : COMT158 Val/ Val . ??????????? ??? 4 Treatment Week 12 15 Patent Application Publication Dec. 27 , 2018 Sheet 4 of 7 US 2018 / 0371542 A1 V OPRM1-asp40 NaltrexoneEffectbyGenotypeOver4Months FIG.3 . OT .. Placebo . OPRM1-asn40 wwwwwwwwww . COMT158MetCarrier : . : wwwwwaptoportante . Days Drinking HeavyPercent Patent Application Publication Dec. 27 , 2018 Sheet 5 of 7 US 2018 / 0371542 A1 OPRM1- asn40 DAT at least one 9 . IIIIIII : : : . ArexoneTAUX + + . * * * ** . H . A . ' ' X . DAT 10 / 10 . viii ! ! ! FIG . 4A Patent Application Publication Dec . 27, 2018 Sheet 6 of 7 US 2018 / 0371542 A1 OPRM1- asp40 DAT at least one 9 Placebo n = 16 Naltrexone n = 17 *. + . ' ' * DAT 10 / 10 Naltrexone = 21 TreatmentWeek 12 16 3 Patent Application Publication Dec . 27 , 2018 Sheet 7 of 7 US 2018 / 0371542 A1 OPRMI-asp40 Month4(EndofStudy) FIG.5 OPRMI-ash40 mmmm ~ ~~ ~ ~~ mmmmmmmmmmmmmmmmmmmmmm Day Drinking Per Drinks US 2018 / 0371542 A1 Dec. 27 , 2018 OPIOID RECEPTOR BLOCKADE IN naltrexone ) that remove these inconsistencies and methods TREATING ALCOHOL USE DISORDERS of detecting susceptibility to opioid receptor antagonist treatment. CROSS -REFERENCE TO RELATED APPLICATION SUMMARY [ 0001] This application claims the benefit of U . S . Provi- [0006 ] This Summary lists several embodiments of the sional Patent Application Ser . No . 62 /525 , 123 , filed Jun . 26 , presently disclosed subject matter, and in many cases, lists 2017 , the disclosure of which is incorporated herein by variations and permutations of these embodiments . This reference in its entirety . Summary is merely exemplary of the numerous and varied embodiments . Mention of one or more representative fea GRANT STATEMENT tures of a given embodiment is likewise exemplary . Such an [0002 ] This invention was made with government support embodiment can typically exist with or without the feature under R01AA017633 and P50 AA010761 , and ( s ) mentioned ; likewise , those features can be applied to K05AA017435 awarded by the National Institute on Alco other embodiments of the presently disclosed subject matter, hol Abuse and Alcoholism . The government has certain whether listed in this Summary or not. To avoid excessive rights in the invention . repetition , this Summary does not list or suggest all possible combinations of such features. TECHNICAL FIELD 10007 ] In some embodiments , the presently disclosed sub ject matter relates to methods and compositions related to 10003 ] The presently disclosed subject matter relates to the use of opioid receptor antagonists in the treatment of treating disorders associated with opioid receptor activity , psychiatric, mental, and /or neurological disorders . particularly to methods for treating disorders associated with [0008 ] In some embodiments , the presently disclosed opioid receptor activity including but not limited to alcohol methods relate to treating psychiatric , mental, and / or neu use disorders using opioid receptor antagonists , and also to rological disorders ( such as , for example , alcohol use dis methods for detecting susceptibility to opioid receptor order (AUD ) ) . In some embodiments , the presently dis antagonist therapy for disorders associated with opioid closed methods comprise assaying the nucleic acid from a receptor activity. subject for the genotype of the dopamine (DA ) -catabolizing enzyme catechol- O -methyltransferase (COMT ) and the BACKGROUND genotype of the opioid mu receptor gene (OPRM1 ) , wherein [ 0004 ] It is well documented that naltrexone is efficacious when one or two alleles encoding a methionine at amino acid in the treatment of alcohol dependence and has been residue 158 of COMT and two alleles encoding an aspara approved by the U . S . Food and Drug Administration for this gine at amino acid residue 40 of OPRM1 is detected or indication since 1994 . Nevertheless, the effect is moderate at wherein two alleles encoding valine at amino acid residue best , and it is recognized that not all individuals with an 158 of COMT and at least one allele encoding an aspartic alcohol use disorder (AUD ) respond to it. Genetic differ acid at amino acid residue 40 of OPRM1 is detected , an ences have been suggested as one factor that might influence opioid receptor antagonist is administered to the subject ; and both response to alcohol and the ability of naltrexone to wherein when one or two alleles encoding a methionine at modify this response . There have been a number of animal amino acid residue 158 of COMT and at least one allele and human clinical laboratory studies, suggesting that a encoding an aspartic acid at amino acid residue 40 of single nucleotide polymorphism ( SNP ) in the mu opioid OPRM1 is detected or wherein two alleles encoding valine gene (OPRM1 ) ( A118G ) leading to a missense asparagine to at amino acid residue 158 of COMT and two alleles encod aspartic acid amino acid substitution at position 40 ing an asparagine at amino acid residue 40 of OPRM1 is ( Asn40Asp ; rs1799971) can lead to differences in alcohol detected , an opioid receptor antagonist is not administered to effects and response to naltrexone. It has been shown that the subject. In some embodiments , the genotype of COMT some of this enhanced alcohol response and drinking behav is assayed prior to administering the opioid receptor antago ior in rodents engineered to have a homologous SNP is nist or wherein the genotype of COMT is assayed after because of increased dopamine release in the nucleus opioid receptor antagonist therapy has commenced , and accumbens, which in general is thought to be a signature of wherein when one or two alleles encoding a methionine at reinforcement and addiction . Of interest, naltrexone has amino acid residue 158 of COMT and at least one allele been shown in animals to both reduce nucleus accumbens encoding an aspartic acid at amino acid residue 40 of dopamine release and to reduce drinking in rodent and OPRM1 is detected or wherein two alleles encoding valine nonhuman primate drinking models . Also of interest, a at amino acid residue 158 of COMT and two alleles encod homologous SNP to that found in humans in the mu opioid ing an asparagine at amino acid residue 40 of OPRM1 is receptor gene occurring naturally in non - human primates detected , the opioid receptor antagonist therapy is discon also appears to confer both sensitivity to alcohol response tinued . In some embodiments , the opioid receptor antagonist and response to naltrexone in the reduction of alcohol effects is a naltrexone . In some embodiments , the genotype of the and consumption . This finding parallels data in human COMT and OPRM1 polymorphisms are detected by a clinical laboratory studies and clinical trials where naltrex nucleic acid amplification process followed by sequencing one appears to exert a stronger effect on those individuals or gel electrophoresis or direct sequencing . with the Asp40 OPRM1 (A118G ) SNP. However, this find [ 0009 ] In some embodiments, the presently disclosed ing is not universal as several reports suggest that it may not methods further comprise assaying the nucleic acid from a be as salient. subject for the genotype of the variable